Excitatory amino acids such as glutamic acid have been shown to be important neurotransmitters (Johnson, R. L.; Koerner, J. F., J. Med. Chem. 1988, 31, 2057), which in excess participate in the sequence of events leading to neuronal damage after cerebral ischemia (Choi, E. W., Trends Neurosci. 1988, 11, 465). One important sub-type of excitatory amino acid receptor is the NMDA-receptor, which is defined by the selective agonist N-methyl-D-aspartic acid (NMDA). Blocking the action of endogenous agonist by the selective NMDA-receptor antagonist 4-(3-phosphonopropyl-2-piperazinecarboxylic acid (CPP) has been shown to prevent ischemic brain damage in gerbils (Boast, C. A. et al., Brain Research, 1988, 442, 345). Also, NMDA-induced convulsions have been prevented by CPP in mice (Lehmann, J. et al., J. Pharmacol. Exp. Ther. 1987, 240, 737). Finally, competitive NMDA antagonists such as CPP have been shown to prevent the Parkinsonian-like symptoms induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in rats (Turski, L. et al., Nature 1991, 349, 414). For these reasons, NMDA-receptor antagonists are considered appropriate for treatment of epilepsy, stroke (Engelsen, B., Acta Neurol Scand. 1986, 74, 337), and neurodegenerative disorders such as Alzheimer's disease (Maragos, W. F. et al., Trends Neurosci. 1987, 10, 65) and Parkinson's disease. More recently, certain NMDA receptor antagonists have been used for the treatment of pain.
Chemical entities known to be competitive NMDA-receptor antagonists contain the α-amino-carboxylic acid and phosphonic acid functionalities separated by a variety of spacer units. An unembellished example is 2-amino-5-phosphonovaleric acid (AP5) (Watkins, J. C.; Evans, R. H., Annu. Rev. Pharmacol. Toxicol. 1981, 21, 165), which contains a saturated carbon chain. More complex examples, which contain elements enhancing structural rigidity and therefore potency, include CPP (see above), cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS-19755) (Lehman, J. et al., J. Pharmacol. Exp. Ther. 1988, 246, 65), and (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP-37849) (Schmutz, M. et al., Abs. Soc. Neurosci. 1988, 14, 864). The compound of {2-[(8,9)-dioxo-2,6-diaza-bicyclo[5.2.0]-non-1 (7)-en-yl]ethyl}phosphonic acid is a NMDA antagonist which, inter alia, prevents NMDA-induced lethality in vivo, and is useful as anticonvulsants and neuroprotectants in situations involving excessive release of excitatory amino acids. See U.S. Pat. No. 5,168,103, incorporated herein by reference in its entirety.
Given the importance of NMDA antagonist, it is clear that improved synthetic routes to {2-[(8,9)-dioxo-2,6-diaza-bicyclo[5.2.0]-non-1 (7)-en-2-yl]ethyl}phosphonic acid are needed. This invention is directed to this, as well as other, important ends.